Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors.
Authors: Manish Sharma, Yasutoshi Kuboki, D. Ross Camidge, Ruth Perets, David Sommerhalder, Noboru Yamamoto, Jair Bar, Apurvasena Parikh, Rui Li, Gladys Morrison Thiele, Martha Raluca Neagu Aristide, Kevin Jay Freise, John D. Powderly
Journal: Journal of Clinical Oncology (2023)

3015 Background: c-Met overexpression is common in non-small cell lung cancer (NSCLC), gastroesophageal adenocarcinoma (GEA), and colorectal cancer (CRC). There is a need for effective therapies that target c-Met–overexpressing tumors, as there are currently no approved options available. The antibody-drug conjugate (ADC) ABBV-400 consists of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. ABBV-400 exhibited sustained antitumor activity in patient-derived xenograft models of c-Met–expressing NSCLC, GEA, and CRC. Herein, we present data from the dose escalation of the first-in-human study of ABBV-400 monotherapy. Methods: A phase 1 dose escalation/expansion study of ABBV-400 has been initiated in patients with advanced solid tumors (NCT05029882). Primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-400, to determine the recommended phase 2 dose, and to assess preliminary efficacy. PK will be characterized for the conjugate, total antibody, and free payload. Adults (≥18 years) with an advanced solid tumor that progressed on standard therapies were enrolled during dose escalation, without restrictions on the basis of c-Met overexpression status. Results: As of January 2023, 47 patients had enrolled in dose escalation with a median follow-up of 6.5 months. Median age was 58 years (range, 34–79), 25 (53%) patients were male, and the most common cancer types were CRC (n=21), NSCLC (n=5), and GEA (n=5). The median number of prior treatment lines was 4 (1–13). Most common hematologic adverse events (AEs) were anemia (66%; grade [G]≥3: 38%), neutropenia (62%; G≥3: 43%), thrombocytopenia (43%; G≥3: 26%), and leukopenia (32%; G≥3: 19%). Nausea (60%, all grade 1–2), fatigue (49%; G≥3: 4%), and vomiting (38%, all grade 1–2) were the most frequent non-hematologic AEs. One patient experienced grade 1 interstitial lung disease. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were dose and exposure dependent. Clinical activity was observed with ABBV-400, with an objective response rate of 24.4% (11/45; 95% CI: 12.9, 39.5). All responses were confirmed partial responses (PR). In addition, 23 patients (50.0%) had stable disease (SD) and 7 (15.2%) had progressive disease. Among patients with CRC, 4/21 (19.0%) had a PR and 13/21 (61.9%) had durable SD, with a disease control rate of 81.0% (95% CI: 58.1, 94.6). Outside of CRC, PRs were observed in patients with NSCLC ( EGFR wildtype and mutant), uterine cancer, and acral melanoma. Conclusions: On the basis of DLTs, a maximum tolerated dose of ABBV-400 was identified. At this dose, safety results appear comparable with other Top1i ADCs. Promising antitumor activity was seen with ABBV-400 across tumor types, justifying further evaluation in the ongoing dose expansion in NSCLC, GEA, and CRC. Clinical trial information: NCT05029882 .